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Histone deacetylase inhibitors synergizes with catalytic inhibitors of EZH2 to exhibit antitumor activity in small cell carcinoma of the ovary, hypercalcemic type Wang, Yemin; Chen, Shary Yuting; Colborne, Shane; Lambert, Galen; Shin, Chae Young; Dos Santos, Nancy; Orlando, Krystal A.; Lang, Jessica D; Hendricks, William P.D.; Marcel B., Bally; et al.

Abstract

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare but extremely lethal malignancy that mainly impacts young women. SCCOHT is characterized by a diploid genome with loss of SMARCA4 and lack of SMARCA2 expression, two mutually exclusive ATPases of the SWI/SNF chromatin-remodeling complex. We and others have identified the histone methyltransferase EZH2 as a promising therapeutic target for SCCOHT, suggesting that SCCOHT cells depend on the alternation of epigenetic pathways for survival. In this study, we found that SCCOHT cells were more sensitive to pan-HDAC inhibitors compared to other ovarian cancer lines or immortalized cell lines tested. Pan-HDAC inhibitors, such as quisinostat, reversed the expression of a group of proteins that were deregulated in SCCOHT cells due to SMARCA4 loss, leading to growth arrest, apoptosis and differentiation in vitro and suppressed tumor growth of xenografted tumors of SCCOHT cells. Moreover, combined treatment of HDAC inhibitors and EZH2 inhibitors at sub-lethal doses synergistically induced histone H3K27 acetylation and target gene expression, leading to rapid induction of apoptosis and growth suppression of SCCOHT cells and xenografted tumors. Therefore, our preclinical study highlighted the therapeutic potential of combined treatment of HDAC inhibitors with EZH2 catalytic inhibitors to treat SCCOHT.

Item Metadata

Title
Histone deacetylase inhibitors synergizes with catalytic inhibitors of EZH2 to exhibit antitumor activity in small cell carcinoma of the ovary, hypercalcemic type
Alternate Title
Targeting HDAC in SCCOHT
Creator
Wang, Yemin; Chen, Shary Yuting; Colborne, Shane; Lambert, Galen; Shin, Chae Young; Dos Santos, Nancy; Orlando, Krystal A.; Lang, Jessica D; Hendricks, William P.D.; Marcel B., Bally; Karnezis, Anthony N.; Hass, Ralf; Underhill, T M; Morin, Gregg B.; Trent, Jeffrey M.; Weissman, Bernard E.; Huntsman, David G.
Contributor
University of British Columbia. Biomedical Research Centre
Date Issued
2018-09-19
Description
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare but extremely lethal malignancy that mainly impacts young women. SCCOHT is characterized by a diploid genome with loss of SMARCA4 and lack of SMARCA2 expression, two mutually exclusive ATPases of the SWI/SNF chromatin-remodeling complex. We and others have identified the histone methyltransferase EZH2 as a promising therapeutic target for SCCOHT, suggesting that SCCOHT cells depend on the alternation of epigenetic pathways for survival. In this study, we found that SCCOHT cells were more sensitive to pan-HDAC inhibitors compared to other ovarian cancer lines or immortalized cell lines tested. Pan-HDAC inhibitors, such as quisinostat, reversed the expression of a group of proteins that were deregulated in SCCOHT cells due to SMARCA4 loss, leading to growth arrest, apoptosis and differentiation in vitro and suppressed tumor growth of xenografted tumors of SCCOHT cells. Moreover, combined treatment of HDAC inhibitors and EZH2 inhibitors at sub-lethal doses synergistically induced histone H3K27 acetylation and target gene expression, leading to rapid induction of apoptosis and growth suppression of SCCOHT cells and xenografted tumors. Therefore, our preclinical study highlighted the therapeutic potential of combined treatment of HDAC inhibitors with EZH2 catalytic inhibitors to treat SCCOHT.
Subject
SCCOHT; SWI/SNF; Chromatin-remodeling complex; Differentiation; HDAC; EZH2; SMARCA4; Ovarian cancer
Genre
Article; Postprint
Type
Text
Language
eng
Date Available
2019-09-19
Provider
Vancouver : University of British Columbia Library
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
DOI
10.14288/1.0372973
URI
http://hdl.handle.net/2429/67672
Affiliation
Medicine, Faculty of; Other UBC; Non UBC; Cellular and Physiological Sciences, Department of; Medical Genetics, Department of; Obstetrics and Gynaecology, Department of; Pathology and Laboratory Medicine, Department of
Peer Review Status
Reviewed
Scholarly Level
Faculty; Other
Rights URI
http://creativecommons.org/licenses/by-nc-nd/4.0/
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Attribution-NonCommercial-NoDerivatives 4.0 International